Real-World Data Support Gut Microbiota as an Independent Driver of Response to ICIs in Lung Cancer, Melanoma

According to results of an observational study of patients with metastatic cancer receiving immune checkpoint inhibitor therapy (ICIs), prior, but not current, use of antibiotic therapy was associated with a lower response rate to treatment and worse overall survival (OS).  The findings from this study were published in JAMA Oncology.¹

Recent evidence showed that the composition of the gut microbiota can influence whether patients with advanced cancer respond to ICIs.² Furthermore, treatment with antibiotics has been previously demonstrated to interfere with the clinical benefit of ICIs in this population of patients.² Nevertheless, additional studies on the impact of antibiotic therapy on the efficacy of ICIs outside of the clinical trial setting — and in patients with a variety of cancer types — are warranted.

This prospective, multicenter, cohort study included unselected patients with cancer consecutively treated with ICIs at 2 tertiary academic medical centers between January 1, 2015, and April 1, 2018.

The objective of this study was to determine whether prior (up to 30 days prior to ICI initiation) or current use of a broad-spectrum antibiotic affected the response rate and OS of patients with advanced cancer receiving ICIs as part of routine clinical practice.

Of the 196 patients included in the study, 29 and 68 patients had received prior or concurrent antibiotic therapy, respectively. In addition, 60% and 20% had a diagnosis of non-small cell lung cancer (NSCLC) and malignant melanoma, respectively, with a diagnosis of clear cell renal cell carcinoma, head and neck squamous cell carcinoma, or transitional cell carcinoma in the remaining patients.

Nearly all patients (96%) had received programmed cell death-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) inhibitors, and this treatment was administered for the first-line treatment of metastatic disease in 62% of patients. Most (81%) patients had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Prior antibiotic therapy was typically administered for 7 days or less, and approximately one-quarter of patients received treatment with corticosteroids.

For the overall patient cohort, median OS was 14.6 months, and the median duration of treatment was 3.3 months. One percent of patients achieved a complete response to ICI treatment, with partial response or stable disease as best response seen in 33% and 12% of patients, respectively.

On univariate analysis, prior antibiotic therapy (hazard ratio [HR], 7.4; 95% CI, 4.3-12.8; P <.001), but not concurrent antibiotic therapy (HR, 0.9; 95% CI, 0.5-1.4; P =.65), was associated with significantly worse OS.

The observation of worse OS in patients receiving prior antibiotic therapy was independent of antibiotic class, patient performance status, or use of corticosteroids.

Furthermore, subgroup analyses showed the impact on OS of prior antibiotic therapy vs no prior antibiotics was independent of tumor type:

• 2.5 months vs 26 months (P <.001): NSCLC
• 3.9 months vs 14 months (P <.001): melanoma
• 1.1 months vs 11 months (P <.001): other tumor types

This finding argues against prior antibiotic therapy as a surrogate for patient comorbidities (ie, chronic airway disease in lung cancer), the study authors commented.

In addition, the response rate for patients not receiving prior antibiotic therapy was nearly double that observed for patients treated with antibiotics before ICI therapy, “an association that is independent from any potential association with comorbidities and corroborates the important link between antibiotic use and response to ICI therapy,” the study authors noted.

Study limitations identified by the researchers included a small sample size and no matched analyses of gut microbiota.

In their concluding remarks, the study authors noted that “although provision of [concurrent antibiotic therapy] appears to be safe in the context of immunotherapy, clinicians should carefully the weigh the pros and cons of prescribing broad-spectrum [antibiotic therapy] prior to ICI treatment. Mechanistic studies are urgently required to investigate [antibiotic therapy]-mediated gut dysbiosis not solely as a prognostic marker but as a therapeutically actionable driver of the anticancer immune response in the context of ICI therapy.”

References

1. Pinato DJ, Howlett S, Ottaviani D, et al. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer [published online September 12, 2019]. JAMA Oncol. doi: 10.1001/jamaoncol.2019.2785
2. Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359:91-97.